Synthesis and properties of imidazo[1,2-a]pyridinium-3-olate. Some revised structures

Article abstract of DOI:10.1016/j.tet.2009.06.116

Reaction of 2-anilinopyridine with chloroacetyl chloride in the presence of N,N-dimethylacetamide resulted in the formation of the mesoion imidazo[1,2-a]pyridinium-3-olate instead of the reported 4-oxopyrimidinium-5-olate. We performed some functionalizat

Full text of DOI:10.1016/j.tet.2009.06.116

Tetrahedron 65 (2009) 7591–7596
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Tetrahedron
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Synthesis and properties of imidazo[1,2-a]pyridinium-3-olate.
Some revised structures
,
Anika Sabine Lindner a, Martin Nieger b, Andreas Schmidt a
*
a Clausthal University of Technology, Institute of Organic Chemistry, Leibnizstrasse 6, D-38678 Clausthal-Zellerfeld, Germany
b University of Helsinki, Laboratory of Inorganic Chemistry, 00014 University of Helsinki, Finland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 June 2009
Received in revised form 23 June 2009
Accepted 25 June 2009
Available online 2 July 2009
Reaction of 2-anilinopyridine with chloroacetyl chloride in the presence of N,N-dimethylacetamide resulted
in the formation of the mesoion imidazo[1,2-a]pyridinium-3-olate instead of the reported 4-oxopyr-
imidinium-5-olate. We performed some functionalizations and present two single crystal X-ray analyses.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Circumdatin A
Mesoions
Mesomeric betaines
Pyrimidinium-olate
1. Introduction
R
O
R
O
R
O
R
O
N
N
N
N
Heterocyclic mesomeric betaines1 are not only interesting
starting materials for heterocyclic as well as natural product syn-
thesis,2 but also form a class of natural products by themselves.3
More than thirty different structural types of mesomeric betaines
were isolated from natural sources, among them conjugated, cross-
conjugated as well as pseudo-cross-conjugated heterocyclic meso-
meric betaines.3 4-Oxopyrimidinium-6-olate 14 belongs to the class
of cross-conjugated heterocyclic mesomeric betaines (CCMB). As
evidenced by a single crystal X-ray analysis, the central pyrimidine
ring of its tetraphenyl derivative is planar with Cs symmetry.5 The
1
O
R
N
R1
O
R
O
R
H
N
N
N
N
N
N
O
O
R2
O
O
OMe
charges are delocalized in separated parts of the common
p-elec-
2
3
4a: R = OMe
4b: R = H
tron system, as the bonds N1–C6 and N3–C4 are essentially single
bonds which are not involved in delocalisation.1,5 Interest has been
focussed on this molecule from the viewpoints of structural and
synthetic organic chemistry6 as well as of materials chemistry. This
betaine has been used as partial structure of photosensitive films7
and polymers.8 Very recently, N-heterocyclic carbenes of this
mesomeric betaine have been described (Scheme 1).9
The isomer of 4-oxopyrimidinium-6-olate 1, the 4-oxopyrimidin-
ium-5-olate 2, has been described as pyrido[1,2-a]pyrimidinium-3-
olates3inthe literature.10 Inaddition, ithasbeenproposedasunusual
partial structure of the alkaloids Circumdatin A and B (4a and 4b,
resp.) which were isolated from the fungus Aspergillus ochraceus.11
Scheme 1. Pyrimidiniumolates 1–3 and the Circumdatins A 4a and B 4b.
In continuation of our interest in heterocyclic mesomeric beta-
ines,12 N-heterocyclic carbenes,13 and molecules which are related to
the proposed structures 4 and 5,14 we reinvestigated the chemistry of
the literature-known betaines 3 and found that these structures must
be revised.
2. Results and discussion
Reaction of 2-anilinopyridine 5 with chloroacetyl chloride in the
presence of N,N-dimethylacetamide at 50 ꢀC yielded the title
compound 6 instead of the previously reported10 pyrido[1,2-a]-
pyrimidinium-3-olate 3 (Scheme 2).
* Corresponding author. Tel.: þ49 5323 723861; fax: þ49 5323 72 2858.
E-mail address: schmidt@ioc.tu-clausthal.de (A. Schmidt).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.06.116

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A.S. Lindner et al. / Tetrahedron 65 (2009) 7591–7596
spectroscopy, these two CO groups differ considerably, as they are
detectable at
¼179 ppm and 158.3 ppm, respectively.
d
N
N
O
The first synthesis of this compound was reported as early as
1971.15 Some imidazolium-4-olates annelated to other rings such as
Besthorn’s red16 are of historical interest, other ring annelations such
as imidazolo[2,3-b]thiazinylium-2-olates,17 imidazo[1,2-c]pyrimidin-
3-olate,18 imidazo[1,2-a]pyridinium-2-olate,19 5,6-dihydrobenzo[h]-
imidazo[1,2-c]quinazolinium-1-olate20 or substitution patterns21
have also been prepared. Pharmacological interest has been focussed
on 5-aryloxyimidazoles which were synthesized as potential in-
hibitor of HIV reverse transcriptase.22
O
O
N
Cl
N
Cl
6
Cl
O
N
N
H
Me
Me
Ph
O
Me
N
5
The mesomeric betaine 6 belongs to the class of mesoions, i.e. to
the conjugated heterocyclic mesomeric betaines. Characteristic for
that class of compounds are common atoms for the positive as well
as the negative charge in the resonance structures (Fig. 2). Mesoion
6 is isoconjugated with the even, non-alternant hydrocarbon dia-
nion depicted in Figure 2, so that this betaine belongs to class no. 4
according to the comprehensive classification system proposed by
Ollis, Stanforth, and Ramsden in 1985.1 Nevertheless, the X-ray data
show that the negative charge is not delocalized in the entire
Cl
O
3
Scheme 2. Reaction of 2-anilinopyridine with chloroacetyl chloride.
The spectroscopic data such as 1H NMR spectra we measured are
identical to those reported. In addition, we performed HMBC,
HSQC, HH-COSY and 15N HMBC measurements. In accordance with
structure 6 and in disagreement to structure 3 a strong coupling
between the methylene group and one of the keto functionalities
was observed by HMBC-NMR measurements, and only a weak
coupling between this CH2-group and the enolate carbon atom. The
p-conjugated system, but that it is separated from the cationic
partial structure by single bonds. Thus, the bond lengths C3–N3A
and N1–C7A (crystallographic numbering, cf. Fig. 1) were de-
termined to be 142.4(5) pm and 137.1(5) pm, respectively.
nitrogen atoms appear at
d
¼ꢁ184.5 and ꢁ218.9 ppm in 15N NMR
spectroscopy. The structure 6 was also confirmed by an X-ray single
crystal analysis, the result of which is shown in Figure 1. Single
crystals were obtained by slow evaporation of 6 in ethanol.
resonance structures
Ph
N
Ph
Ph
N
N
N
O
N
O
N
O
etc
O
O
O
Cl
Cl
Cl
charge distribution according to mesomeric structures:
sites for positive charges
sites for negative charges
sites for positive and negative charges
Ph
Cl
isoconjugate equivalent:
Figure 2. Classification of mesoion 6.
The formation of 6 obviously proceeds by reaction of chloro-
acetyl chloride with the bisnucleophile 5 via pyridinium salt 7 and
mesoion 8 which is formed on deprotonation of 7 under the reaction
conditions. The resulting mesoion 8 then attacks a second molecule
of chloroacetyl chloride to give 6 via cation 8A (Scheme 3).
In a reverse process, the mesomeric betaine 6 forms the stable
salt 9 in quantitative yields on treatment with aqueous HBF4 in
chloroform (Scheme 4). In accordance to this structure, the reso-
nance frequencies of the CH2-group are shifted from 45.2 ppm to
54.7 ppm in the 13C-spectra and from 4.80 ppm to 5.48 ppm in the
1H-spectra. In the IR spectra a sharp carbonyl absorption band at
1775 cmꢁ1 was detected. Triethylamine caused decomposition of
this salt.
Figure 1. Molecular drawing of mesoion 6.
The phenyl substituent is twisted out of the plane of the pyr-
idinium ring. Thus, the dihedral angles of C7A–N1–C11–C16 (crys-
tallographic numberings) and C2–N1–C11–C12 are ꢁ53.4(6)ꢀ and
ꢁ50.7(6)ꢀ, respectively. In addition, neither the propenone-3-olate
partial structure delocalizing the negative charge nor the imida-
zopyridinium ring system are planar: As examples, dihedral angles
of ꢁ6.1(8)ꢀ [O2–C2–C3–C31] and 9.1(6)ꢀ [C31–C3–N3A–C4] were
determined. The bond distances of C2–C3 and C3–C31 are
141.4(6) pm and 142.4(6) pm, respectively, and possess values be-
tween single and double bonds [148 pm and 132 pm, respectively].
The bond distances of C2–O2 and C31–O31 are almost identical
[123.5(5) pm and 122.5(5) pm, respectively] and correspond to
values between C–O single- and C]O double-bonds. In accordance
with the delocalized negative charge no C]O absorption at
1700 cmꢁ1 was detectable by IR spectroscopy. In NMR
The chlorine atom of 6 is susceptible to a variety of nucleophilic
substitutions. Thus, 10a–k were prepared (Scheme 5, Table 1). Re-
actions of 6 with amines were realised without any base or catalyst.
Conversions of 6 with alcohols needed sodium alcoholate or

A.S. Lindner et al. / Tetrahedron 65 (2009) 7591–7596
7593
Table 1
Substituted mesoions 10a–k
Cl
O
Entry
1
Nucleophile
NH2
NH2
Product
Yielda (%)
53
Cl
-H
Cl
N
N
N
O
N
O
5
10a
2
10b
51
7
8
O
N
Cl
Cl
N
3
10c
97
NMe
Cl
4
5
10d
10e
62
21
NH2
-H
N
6
OH
O
H
O
Cl
8A
6
7
8
10f
79
90
92
OH
Scheme 3. Proposed mechanism for the formation of 6.
H3C OH
HO
10g
10h
HBF4
N
N
O
6
CHCl3
BF4
OH
9
9
10i
10j
32
20
Scheme 4. Formation of salt 9.
10
N
O
Nuc
Ph
N
N
O
6
O
11
10k
50
H2N
O
Nuc
10a-k
Scheme 5. Nucleophilic substitutions.
a
Yields refer to those of pure isolated products.
potassium carbonate as bases. The N-methylpiperazine derivative
has been described10a as a derivative of 4-oxopyrimidinium-5-olate
3 so that its structure has also to be revised to10c. Compound 10j is
a pyridinium salt with chloride as anion.
The structure 10h was confirmed by an X-ray single crystal
analysis. Single crystals were obtained by slow evaporation of 10h
in methanol (Fig. 3). One of the two independent crystallographic
molecules is shown. The minor component of the disordered allyl-
oxy-group is omitted for clarity, and data for the second molecule
are given in brackets.
The dihedral angles of C2–N1–C11–C16 (crystallographic num-
bering) and C7A–N1–C11–C12 are ꢁ48.7(4)ꢀ and ꢁ51.3(4)ꢀ
[ꢁ50.6(4)ꢀ and ꢁ51.5(4)ꢀ], respectively. Moreover, torsion angles of
4.7(5)ꢀ [5.8(4)ꢀ] [O2–C2–C3–C31] and ꢁ3.0(4)ꢀ [–4.2(6)ꢀ] [C31–C3–
N3A–C4] were determined. In analogy to 6 the allylic derivate 10h
has a delocalized negative charge.
In summary, reaction of 2-anilinopyridine with chloroacetyl
chloride in the presence of N,N-dimethylacetamide gives imi-
dazo[1,2-a]pyridinium-3-olate instead of 4-oxopyrimidinium-5-
olate. We report functionalizations by nucleophilic substitution
reactions and present two single crystal X-ray analyses.
3. Experimental
3.1. General
Figure 3. Molecular drawing of mesoion 10h.
200 and 400 MHz at 20 ꢀC. The chemical shifts are reported in ppm
relative to internal tetramethylsilane (
d
¼0.00). Multiplicities are de-
The 1H and 13C NMR spectra were recorded on Bruker ARX-400
and DPX-200 spectrometers and were taken in CDCl3 and DMSO-d6 at
scribed by using the following abbreviations: s¼singlet, d¼doublet,
t¼triplet, q¼quadruplet, h¼heptet, m¼multiplet, br¼broad. The

7594
A.S. Lindner et al. / Tetrahedron 65 (2009) 7591–7596
mass spectra (EIMS) were measured with a Hewlett-Packard HP
5989B or a Varian SAT2100T with GC3900. Melting points are un-
corrected. The CHN analyses were performed in the Institute of
Technical Chemistry of the Clausthal University of Technology.
3.4. 2-Oxo-1-phenyl-2,3-dihydro-1H-imidazo[1,2-a]-
pyridinium (9)
A sample of 0.143 g (0.5 mmol) of the betaine 6 was dissolved in
2 mL of chloroform and then treated with tetrafluoroboric acid
(40%, 0.5 mL). After the mixture had been stirred for 30 min at room
temperature the solvents were evaporated to leave a reddish solid
which was recrystallized from ethanol.
3.2. X-ray crystal structure analyses of 6 and 10h
6: colorless crystals, C15H11ClN2O2, M¼286.71, crystal size
0.40ꢂ0.20ꢂ0.05 mm, monoclinic, space group P21/c (no. 14):
Yield: quantitative; 1H NMR (400 MHz, MeOD):
d
¼5.45 (s, 2H, C-
a¼3.896(1) Å,
b¼22.380(3) Å,
c¼14.444(1) Å,
b
¼97.73(1)ꢀ,
3), 7.33 (d, J¼8.8 Hz, 1H, 8-H), 7.49 (m, 2H, 20-H), 7.58–7.69 (m, 4H,
V¼1247.9(4) Å3,
Z¼4,
r
(calcd)¼1.526 Mg mꢁ3
,
F(000)¼592,
30-H, 40H, 6-H), 8.38 (t, J¼8.2 Hz, 1H, 7-H), 8.83 (d, J¼6 Hz, 1H, 5-H).
m
¼0.308 mmꢁ1, 9231 reflections (2qmax¼50ꢀ) measured on a Bruker-
13C NMR (100 MHz, MeOD):
d
¼55.1 (C-3), 110.5 (C-8), 120.2 (C-6),
Nonius Kappa-CCD diffractometer at 123(2) K using MoK
a
radiation
127.6 (2C, C-20), 130.6 (C-10), 139.8 (3C, C-30, C-40), 139.9 (C-5), 148.0
~
(
l
¼0.71073 Å), 2203 unique [Rint¼0.1049] used for structure solution
(C-7), 153.5 (C-9), 167.8 (C-2). IR (KBr):
n
¼ 3332, 1772, 1646, 1586,
(Direct Methods, SHELXS-9723) and refinement (full-matrix least-
1514, 1397, 1339, 1310, 1225, 1065, 1025, 766 cmꢁ1 ESI-MS: m/z
squares on F2, SHELXL-9723) with 181 parameters, H-atoms with
(%)¼211.1 (100), 509 (35).
a riding model, R1 (I>2
s
(I))¼0.0704, wR2 (all data)¼0.1725, largest
diff. peak and hole 0.449 and ꢁ0.413 e Åꢁ3
.
3.5. General procedure for the nucleophilic substitutions on
imidazo[1,2-a]pyridinium-3-olate 6 to 10a–k
10h: colorless crystals, C18H16N2O2$0.25 MeOH, M¼316.34, crystal
size 0.50ꢂ0.25ꢂ0.15 mm, triclinic, space group P-1 (no. 2):
a¼10.036(1) Å,
b¼12.566(3) Å,
c¼12.680(1) Å,
a
¼89.79(1)ꢀ,
Z¼4,
3.5.1. Amine derivates
b
¼85.74(1)ꢀ,
g
¼72.30(1)ꢀ,
V¼1518.9(2) Å3,
Samples of 0.143 g (0.5 mmol) of betaine 6 and 1.5 mmol of the
corresponding amine were dissolved in 5 mL of chloroform. The
reaction mixture was then heated for 1 h at 50 ꢀC. Evaporation of
the solvent in vacuo gave a solid residue which was purified by
flash column chromatography [silica gel, ethyl acetate] yielding the
products 10a–d.
r
(calcd)¼1.383 Mg mꢁ3, F(000)¼666,
m
¼0.096 mmꢁ1, 15,602 re-
flections (2qmax¼55ꢀ) measured on a Bruker-Nonius Kappa-CCD
diffractometer at 123(2) K using MoK
a
radiation (l¼0.71073 Å), 6815
unique [Rint¼0.0265] used for structure solution (Direct Methods,
SHELXS-9723) and refinement (full-matrix least-squares on F2,
SHELXL-9723) with 424 parameters and 56 restraint, H-atoms with
a riding model, R1 (I>2
s
(I))¼0.0669, wR2 (all data)¼0.1539, largest
3.5.2. 3-(2-(Butylamino)acetyl)-1-phenyl-1H-imidazo[1,2-a]-
pyridinium-2-olate (10a)
diff. peak and hole 0.658 and ꢁ0.611 e Åꢁ3. The allyloxy groups are
disordered.
n-Butylamine was used; yield: 0.09 g (53 %), mp: 120–123 ꢀC; 1H
Crystallographic data (excluding structure factors) for the
structures reported in this work have been deposited with the
Cambridge Crystallographic Data Centre as supplementary publi-
cation no. CCDC-729165 (6) and CCDC-729166 (10h). Copies of the
data can be obtained free of charge on application to The Director,
CCDC, 12 Union Road, Cambridge DB2 1EZ, UK (Fax: þ1223 336–
033; e-mail:deposit@ccdc.cam.ac.uk).
NMR (200 MHz, CDCl3):
d
¼0.91 (t, J¼7.2 Hz, 3H, 7
*
-H),1.23–1.43 (m,
2H, 6 -H), 1.48–1.63 (m, 2H, 5
*
*
-H), 2.56 (br s, 1H, NH), 2.69 (t,
J¼7.0 Hz, 2H, 4
*
-H), 4.11 (s, 2H, 2 ), 7.08–7.32 (m, 2H, Harom.), 7.46–
*
7.65 (m, 6H, Harom.), 10.18 (d, J¼8.2 Hz, 1H, 5-H). 13C NMR (50 MHz,
CDCl3):
*
d
¼14.0 (C-7
*
), 20.4 (C-6
*
), 32.4 (C-5
*
), 49.5 (C-4 ), 55.9 (C-
*
2
), 102.4 (C-3), 106.7 (C-8), 116.6 (C-6), 127.1 (2C, C-20), 129.3 (C-40),
129.7 (C-5), 129.9 (2C, C-30), 131.8 (C-10), 132.1 (C-7), 136.6 (C-9),
~
158.3 (C-2), 186.8 (C]O). IR (KBr):
n
¼ 3420, 2042, 2926, 2868,
3.3. 3-(2-Chloroacetyl)-1-phenyl-1H-imidazo[1,2-a]-
pyridinium-2-olate 6
1658, 1610, 1510, 1441, 1308, 1241, 1206, 1116, 1079, 1049, 921, 771,
711 cmꢁ1. MS: 324 [MþHþ](100), 252 (90), 237 (20), 210 (75), 181
(20), 77 (45). HR-ESI-MS calcd for C19H22N3O2: 324.1712; found:
324.1711. Anal. cCalcd for C19H21N3O2$2H2O: C, 63.7; H, 7.0; N, 11.7.
Found: C, 64.2; H, 5.7; N, 11.4.
A sample of 0.851 g (5 mmol) of 2-anilinopyridine was sus-
pended in 5 mL of anhyd benzene. After addition of 1.07 mL (1.0 g,
11.5 mmol) of N,N-dimethylacetamide, 0.92 mL (1.3 g,11.5 mmol) of
2-chloroacetyl chloride was added dropwise over a period of
10 min. The reaction mixture was heated at 50 ꢀC for 1 h. After
evaporation of the solvent in vacuo the residue was dissolved in
chloroform and washed two times with water and dried over
Na2SO4. Evaporation of the solvent in vacuo gave a solid which was
purified by recrystallisation from ethanol.
3.5.3. 3-(2-(Isobutylamino)acetyl)-1-phenyl-1H-imidazo[1,2-a]-
pyridinium-2-olate (10b)
iso-Butylamine was used; yield: 0.083 g (0.256 mmol, 51%) mp:
142–145 ꢀC; 1H NMR (200 MHz, CDCl3):
CH3), 0.96 (s, 3H, CH3), 1.69–1.92 (m, 1H, CH), 2.09 (br s, 1H, NH),
d
¼0.95 (d, J¼6.6 Hz, 6H,
2.51 (d, J¼6.8 Hz, 2H, 4
*
-H), 4.11 (s, 2H, 1 -H), 7.05–7.25 (m, 2H,
*
Yield: 0.714 g (2.5 mmol, 50%); mp: 192–193 ꢀC (lit10a: 193.5–
Harom.), 7.43–7.65 (m, 6H, Harom.), 10.20 (d, J¼6.8 Hz, 1H, 5-H). 13C
195.5 ꢀC); 1H NMR (400 MHz, CDCl3):
d
¼4.84 (s, 2H, CH2Cl), 7.15
NMR (50 MHz, CDCl3):
d
¼20.7 (2C, CH3), 27.0 (CH), 56.2 (CH2), 57.9
(dt, J¼8.61, 1.08 Hz, 1H, 8-H), 7.23–7.27 (m, 1H, 6-H), 7.44–7.46
(m, 2H, 20-H), 7.50–7.54 (m, 1H, 40-H), 7.56–7.61 (m, 3H, 30-H, 7-
H), 10.13 (dt, J¼6.65, 0.93 Hz, 1H, 5-H). 13C NMR (100 MHz,
(CH2), 102.4 (C-3), 106.7 (C-8), 116.5 (C-6), 127.1 (2C, C-20), 129.3 (C-
40), 129.7 (C-5), 129.9 (2C, C-30), 131.9 (C-10), 132.0 (C-7), 136.5 (C-9),
~
158.3 (C-2),187.0 (C]O). IR (KBr):
n
¼ 3419, 3047, 2951, 1661,1608,
CDCl3:
d
¼46.5 (CH2Cl), 102.1 (C-3), 106.9 (C-8), 116.9 (C-6), 127.0
1510, 1439, 1307, 1240, 1206, 1114, 1079, 1048, 770, 711 cmꢁ1. MS:
323 [Mþ](20), 280 (10), 252 (90), 237 (40), 223 (70), 210 (100), 181
(20), 77 (90). HR-ESI-MS calcd for C19H22N3O2: 324.1712; found:
324.1711. Anal. cCalcd for C19H21N3O2$2.5H2O: C, 61.94; H, 7.11; N,
11.40. Found: C, 61.71; H, 5.41; N, 11.03.
(2C, C-20), 129.5 (C-40), 130.0 (3C, C-30, C-5), 131.5 (C-10), 133.1 (C-
7), 137.2 (C-9), 158.3 (C-2), 179 (C]O). 15N NMR (40 MHz,
CDCl3):
d
¼ꢁ184.5 (N-5), ꢁ218.9 (N-1). MS: m/z (%)¼286
(70)[Mþ], 237 (100), 208 (5), 181 (15), 168 (5), 119 (5), 77 (60). IR
(KBr)¼3084, 1678, 1633, 1509, 1440, 1385, 1303, 1269, 1240,
1204, 1121, 1076, 772, 703 cmꢁ1
.
HR-ESI-MS calcd for
3.5.4. 3-(2-(4-Methylpiperazin-1-yl)acetyl)-1-phenyl-1H-
imidazo[1,2-a]pyridinium-2-olate (10c)
C15H11N2O2Cl: 286.0509; found: 286.0509. Anal. Calcd for
C15H11N2O2Cl: C, 62.84; H, 3.87; N, 9.77. Found: C, 62.69; H,
3.33; N, 9.40.
1-Methylpiperazine was used; yield: 0.170 g (0.485 mmol, 97%)
mp: 167 ꢀC (dec); 1H NMR (200 MHz, CDCl3):
d
¼2.30 (s, 3H, CH3),

A.S. Lindner et al. / Tetrahedron 65 (2009) 7591–7596
7595
2.52 (br s, 4H,
b-Pip-H), 2.76 (br s, 4H,
a
-Pip-H), 3.94 (s, 2H, CH2),
3.5.8. 3-(2-Methoxyacetyl)-1-phenyl-1H-imidazo[1,2-a]-
7.12–7.30 (m, 2H, Harom.), 7.45–7.66 (m, 6H, Harom.), 10.23 (d,
pyridinium-2-olate (10g)
J¼6.8 Hz, 1H, 5-H). 13C NMR: (50 MHz, CDCl3):
d
¼44.9 (CH3), 52.6
Methanol was used; yield: 0.127 g (0.45 mmol, 90 %); mp:
(2C,
a
-Pip-C), 53.9 (2C,
b
-Pip-C), 62.5 (CH2), 102.0 (C-3), 105.7 (C-8),
181 ꢀC; 1H NMR (200 MHz, CDCl3):
d
¼3.54 (s, 3H, CH3), 4.76 (s, 2H,
115.6 (C-6), 126.1 (2C, C-20), 128.4 (C-40), 129.0 (C-5), 129.0 (2C, C-
CH2), 7.13–7.27 (m, 2H, Harom.), 7.43–7.65 (m, 6H, Harom.), 10.82 (d,
30), 130.9 (C-10), 131.1 (C-7), 135.6 (C-9), 157.3 (C-2), 183.8 (C]O). IR
J¼6.4 Hz, 1H, 5-H). 13C NMR (50 MHz, CDCl3):
¼59.4 (CH3), 75.2
d
(KBr):
n
¼ 3423, 3111, 3039, 2963, 2927, 2791, 1678, 1613, 1510,
(CH2), 101.8 (C-3), 106.8 (C-8), 116.7 (C-6), 127.0 (2C, C-20), 129.4 (C-
~
1449, 1344, 1262, 1204, 1101, 1016, 801, 768, 710 cmꢁ1. MS: 351
[MþHþ](60), 280 (20), 252 (90), 237 (30), 223 (40),113 (50), 77 (35),
70 (100). HR-ESI-MS calcd for C20H23N4O2: 351.1821; found:
351.1821. Anal. cCalcd for C20H23N4O2: C, 65.20; H, 6.56; N, 15.20.
Found: C, 64.84; H, 6.19; N, 15.17.
40), 129.7 (C-5), 129.9 (2C, C-30), 131.8 (C-10), 132.2 (C-7), 136.8 (C-9),
~
n
158.2 (C-2),184.4 (C¼O). IR (KBr):
¼ 3442, 3107, 3060, 2988, 2945,
2825,1690,1604,1507,1476,1458,1440,1358,1323,1242,1202,1107,
1044, 997, 905, 770 cmꢁ1. MS: 283 [MþHþ](100), 267 (20), 252 (40),
237 (90), 181 (20), 77 (40). HR-ESI-MS calcd for C16H15N2O3:
283.1083; found: 283.1084. Anal. cCalcd for C16H14N2O3 (282.29): C,
68.07; H, 5.00; N, 9.92. Found: C, 67.74; H, 4.51; N, 10.02.
3.5.5. 3-(2-(Benzylamino)acetyl)-1-phenyl-1H-imidazo[1,2-a]-
pyridinium-2-olate (10d)
Benzylaminewasused; yield:0.109 g (0.31 mmol,62%); mp:148–
3.5.9. 3-(2-Allyloxyacetyl)-1-phenyl-1H-imidazo[1,2-a]-
pyridinium-2-olate (10h)
150 ꢀC; 1H NMR (200 MHz, CDCl3):
d
¼2.61 (s, 1H, NH), 3.89 (s, 2H,
CH2), 4.15 (s, 2H, CH2), 7.05–7.65 (m, 13H, Harom.), 10.15–10.19 (m, 1H,
5-H).13C NMR (50 MHz, CDCl3):
¼53.7 (CH2), 55.5 (CH2),102.4 (C-3),
106.7 (C-8),116.6 (C-6),126.8(C-8 , C-
),127.1 (2C, C-20),128.3(4C, C-6
), 129.4 (C-40), 129.7 (C-5), 130.0 (2C, C-30), 131.8 (C-10), 132.1 (C-7),
Allylalcohol was used; yield: 0.141 g (0.46 mmol, 92 %); mp:
d
126–129 ꢀC; 1H NMR (200 MHz, CDCl3):
d
¼4.20 (dt, J¼5.8, 1.2 Hz,
*
*
2H, 1
*
-H), 4.83 (s, 2H, CH2), 5.17–5.40 (m, 2H, 3 -H), 5.92–6.12 (m,
*
7
*
1H, 2
*
-H), 7.12–7.28 (m, 2H, Harom.), 7.41–7.64 (m, 6H, Harom.), 10.16–
136.6 (C-9),140.3 (C-5
*
),158.2 (C-2),186.4 (C]O). IR (KBr): ¼ 3334,
10.20 (m, 1H, 5-H). 13C NMR (50 MHz, CDCl3):
(CH2), 101.8 (C-3), 106.7 (C-8), 116.7 (C-6), 117.5 (C-3
20),129.3 (C-40),129.7 (C-5),130.7 (2C, C-30),131.8 (C-10), 132.1 (C-7),
d¼72.5 (C-1 ), 72.6
*
~
n
3054, 2926, 1667, 1606, 1511, 1439, 1239, 1206, 1057, 756, 710 cmꢁ1
.
*
), 127.0 (2C, C-
MS: m/z (%)¼358 [MþHþ](60), 266 (30), 252 (100), 237 (30), 210 (70),
181 (20), 91 (70), 77 (20). HR-ESI-MS calcd for C22H19N3O2: 358.1556;
found: 358.1557. Anal. cCalcd for C22H19N3O2$1H2O: C, 70.38; H, 5.64;
N, 11.12. Found: C, 70.61; H, 4.78; N, 11.02.
134.6 (C-2 ), 136.7 (C-9), 158.1 (C-2), 184.5 (C]O). IR (KBr):
*
~
n
¼ 3424, 3057, 2859,1688,1507,1456,1337,1239,1204,1118,1046,
904, 767, 713 cmꢁ1 MS: 309 [MþHþ](100), 252 (90), 237 (85), 223
(15), 210 (20),181 (30), 77 (80). HR-ESI-MS: calcd for C18H16N2O3Na:
331.1059; found: 331.1068. Anal. cCalcd for C18H16N2O3: C, 70.12; H,
5.23; N, 9.09. Found: C, 69.61; H, 5.25; N, 8.79.
3.5.5.1. Aliphatic alcohol derivates. Portions of 0.056 g (2.4 mmol)
of sodium were dissolved in 10 mL of the corresponding alcohols.
Then, 0.143 g (0.5 mmol) of the betaine 6 was added and the re-
action mixture was refluxed for 3 h. Evaporation of the solvent in
vacuo gave solids which were purified by flash column chroma-
tography [silica, ethyl acetate] to give the products 10e–g.
3.5.10. 3-(2-Phenoxyacetyl)-1-phenyl-1H-imidazo[1,2-a]-
pyridinium-2-olate (10i)
A sample of 0.286 g (1 mmol) of the betaine 6 was dissolved in
15 mL of anhyd ethanol. After addition of 0.138 g (1 mmol) of K2CO3
and 0.094 g (1 mmol) of phenol the reaction mixture was refluxed
for 4 h. Evaporation of the solvent in vacuo gave a solid residue
which was purified by flash column chromatography [silica gel,
ethyl acetate] to give product 10i.
3.5.6. 3-(2-Isopropoxyacetyl)-1-phenyl-1H-imidazo[1,2-a]-
pyridinium-2-olate (10e)
iso-Propanol was used; yield: 0.032 g (0.103 mmol, 21%) mp:
126 ꢀC (dec); 1H NMR (200 MHz, CDCl3):
d
¼1.27 (d, J¼6.2 Hz, 6H,
CH3), 3.73–3.86 (m, 1H, CH), 4.82 (s, 2H, CH2), 7.11–7.26 (m, 2H,
Harom.), 7.44–7.65 (m, 6H, Harom.), 10.09 (d, J¼4.6 Hz, 1H, 5-H). 13C
Yield: 0.111 g (0.32 mmol, 32 %); mp: 203 ꢀC (dec); 1H NMR
(200 MHz, CDCl3):
7.14–7.35 (m, 4H, Harom.), 7.46–7.67 (m, 6H, Harom.), 10.16 (dt, J¼6.6,
1.0 Hz, 1H, 6-H). 13C NMR (50 MHz, CDCl3):
d
¼5.39 (s, 2H, CH2), 6.90–7.09 (m, 3H, Harom.),
NMR (50 MHz, CDCl3):
d
¼22.0 (2C, CH3), 71.0 (CH), 72.2 (CH2), 101.9
(C-3), 106.7 (C-8), 116.7 (C-6), 127.0 (2C, C-20), 129.3 (C-40), 129.7 (C-
d¼70.0 (CH2), 102.0 (C–
5), 129.9 (2C, C-30), 131.8 (C-10), 132.0 (C-7), 136.7 (C-9), 158.1 (C-2),
C]O), 106.9 (C-3), 114.7 (2C, C-II), 116.8 (C-5), 120.8 (C-IV), 127.1
(2C, C-20), 129.3 (2C, C-III), 129.5 (C-40), 129.9 (C-6), 130.1 (2C, C-30),
131.7 (C-10), 132.5 (C-4), 137.1 (C-2), 158.6 (C-I), 163.1 (C–Oꢁ), 182.3
~
~
185.2 (C]O). IR (KBr):
n
¼ 3424, 3111, 3053, 2970, 2925, 1691,
1608, 1508, 1454, 1362, 1318, 1240, 1124, 763, 712 cmꢁ1. MS: 311
[MþHþ](50), 267 (40), 252 (100), 237 (100), 210 (20), 181 (30), 77
(60). HR-ESI-MS calcd for C18H19N2O3: 311.1396; found: 311.1396.
Anal. cCalcd for C18H18N2O3 (310.35): C, 69.66; H, 5.85; N, 9.03.
Found: C, 69.11; H, 5.43; N, 9.13.
(C]O). IR (KBr):
n
¼ 3424, 2924, 1675, 1609, 1504, 1456, 1300,
1266, 1235, 1207, 1081, 1053, 1028, 901, 752 cmꢁ1. MS: 344
[Mþ](90), 237 (100), 210 (80), 181 (40), 169 (20), 94 (15), 77 (90).
HR-ESI-MS calcd for C21H16N2O3Na: 367.1059; found: 367.1063.
Anal. cCalcd for C21H16N2O3 (344.2): C, 73.24; H, 4.68; N, 8.13.
Found: C, 72.78; H, 4.26; N, 8.23.
3.5.7. 3-(2-Ethoxyacetyl)-1-phenyl-1H-imidazo[1,2-a]-
pyridinium-2-olate (10f)
Ethanol was used; yield: 0.117 g (0.395 mmol, 79 %) mp: 178–
3.5.11. 1-Phenyl-3-2-(pyridinium)-1H-imidazo[1,2-a]pyridinium-2-
olate chloride (10j)
179 ꢀC; 1H NMR (200 MHz, CDCl3):
d
¼1.32 (t, J¼7.0 Hz, 3H, CH3CH2),
3.70 (q, J¼7.0 Hz, 2H, CH3CH2), 4.81 (s, 2H, CH2), 7.11–7.29 (m, 2H,
A sample of 0.2 mL (2.5 mmol) of pyridine was added to a solu-
tion of 0.143 g (0.5 mmol) of the betaine 6 and 5 mL of chloroform.
The reaction mixture was then refluxed for 4 h. After cooling to
room temperature the reaction mixture was extracted with 10 mL
of water. Evaporation of the solvent in vacuo gave a reddish solid.
Yield: 0.037 g (0.1 mmol, 20 %); mp: 185 ꢀC (dec); 1H NMR
Harom.), 7.45–7.65 (m, 6H, Harom.), 10.19 (d, J¼6.6 Hz, 1H, 5-H). 13C
NMR (50 MHz, CDCl3):
d
¼15.2 (CH3CH2), 61.0 (CH3CH2), 73.3 (CH2),
101.9 (C-3), 106.7 (C-8), 116.7 (C-6), 127.0 (2C, C-20), 129.3 (C-40),
129.7 (C-5), 130.0 (2C, C-30), 131.8 (C-10), 132.1 (C-7), 136.7 (C-9),
~
158.2 (C-2), 184.8 (C]O). IR (KBr):
n
¼ 3110, 3061, 2970, 2865,
1685, 1631, 1506, 1457, 1424, 1340, 1319, 1240, 1204, 1121, 1049, 901,
768, 713 cmꢁ1. MS: 297 [MþHþ](100), 252 (60), 237 (65), 181 (20),
77 (25). HR-ESI-MS: calcd for C17H17N2O3: 297.1239; found:
297.1240. Anal. cCalcd for C17H16N2O3 (296.32): C, 68.91; H, 5.44; N,
9.45. Found: C, 68.41; H, 5.06; N, 9.47.
(200 MHz, CDCl3):
7.50–7.73 (m, 5H, Harom.), 7.82–7.93 (m,1H, Harom.), 8.10–8.18 (m, 2H,
d
¼6.15 (s, 2H, CH2), 7.24–7.43 (m, 2H, Harom.),
b
-Py-H), 8.62–8.73 (m, 1H,
g
-Py-H), 8.96–9.00 (m, 2H,
a
-Py-H), 9.74
¼67.1 (CH2),103.0
-Py-C),
(d, J¼6.4 Hz,1H, 5-H). 13C NMR (50 MHz, CDCl3):
d
(C-3), 109.2 (C-8), 118.9 (C-6), 128.7 (2C, C-20), 128.8 (2C,
b

7596
A.S. Lindner et al. / Tetrahedron 65 (2009) 7591–7596
131.0 (2C, C-40, C-5), 131.3 (2C, C-30), 133.0 (C-10), 136.5 (C-7), 139.9
(C-9),147.2 (g-Py-C),147.7 (2C, a-Py-C),160–8 (C-2),175.6 (C]O). IR
3. (a) Schmidt, A. Adv. Heterocycl. Chem. 2003, 85, 67; (b) Schmidt, A. Curr. Org.
Chem. 2004, 8, 653.
4. Friedrichsen, W.; Kappe, T.; Bo¨ttcher, A. Heterocycles 1982, 19, 1083.
5. Kratky, C.; Kappe, T. J. Heterocycl. Chem. 1981, 18, 881.
6. (a) 1,4-Dipolar cycloadditions: Gotthardt, H.; Schenk, K. H. Chem. Ber. 1985, 118,
4567; (b) Cycloadditions to stable peroxides: Gotthardt, H.; Schenk, K. H. Tet-
rahedron Lett. 1983, 24, 4669; (c) Rearrangements: Kappe, T.; Golser, W. Chem.
Ber. 1976, 109, 3668.
7. (a) Theis, A.; Ritter, H. Des. Monomers Polym. 2001, 4, 177; (b) Go¨rtz, V.; Ritter, H.
Macromolecules 2002, 35, 4558.
~
(KBr):
n
¼ 3405, 3048, 1670, 1602, 1505, 1446, 1201, 1084, 1045,
764, 708 cmꢁ1. MS: m/z (%)¼330 [Mþ](10), 288 (60), 237 (100), 181
(30), 77 (50). HR-ESI-MS calcd for C20H16N3O2: 330.1243; found:
330.1248. Anal. cCalcd for C20H16N3O2Cl$3.5H2O: C, 56.01; H, 5.36;
N, 9.80. Found: C, 56.14; H, 4.73; N, 9.86.
8. (a) Deutschmann, T.; Ritter, H. Macromol. Rapid Commun. 1996, 17, 723; (b)
Ritter, H.; Sperber, R. Macromol. Rapid Commun. 1995, 16, 407.
9. Ce´sar, V.; Lugan, N.; Lavigne, G. J. Am. Chem. Soc. 2008, 130, 11286.
3.5.12. 3-(2-(2-Ethoxy-2-oxoethylamino)acetyl)-1-phenyl-1H-
imidazo-[1,2-a]pyridinium-2-olate (10k)
´
ˇˇ´
´
ˇ
´
´
10. (a) Hulinska, H.; Budesınky, J.; Holubek, J.; Matousova, O.; Frycova, H.; Protiva,
M. Collect. Czech. Chem. Commun. 1989, 54, 1376; (b) Bacque´, E.; El Qacemi, M.;
Zard, S. Z. Org. Lett. 2004, 6, 3671.
A sample of 0.143 g (0.5 mmol) of the betaine 6, 0.140 g
(0.5 mmol) of glycine ethyl ester hydrochloride and 0.14 mL
(0.101 g, 1 mmol) of triethylamine were suspended in 10 mL of
acetonitrile and refluxed for 4 h. Evaporation of the solvent in vacuo
gave a solid residue which was purified by flash column chroma-
tography [silica gel, ethyl acetate] to give the product 10k.
Yield: 0.088 g (0.25 mmol, 50%); mp: 114–116 ꢀC; 1H NMR
11. Rahbaek, L.; Breinhold, J.; Frisvad, J. C.; Christophersen, C. J. Org. Chem. 1999, 64,
1689.
12. Recent example: Albrecht, M.; Schneider, O.; Schmidt, A. Org. Biomol. Chem.
2009, 7, 1445.
13. (a) Lindner, A. S.; Schmidt, A. Synlett 2008, 2961; (b) Schmidt, A.; Snovydovych,
B. Synthesis 2008, 2798; (c) Schmidt, A.; Snovydovych, B.; Hemmen, S. Eur. J.
Org. Chem. 2008, 4313.
14. (a) Schmidt, A.; Gholipour Shilabin, A.; Lindner, A. S.; Nieger, M. Tetrahedron
2008, 64, 2048; (b) Schmidt, A.; Gholipour Shilabin, A.; Namyslo, J. C.; Nieger,
M.; Hemmen, S. Eur. J. Org. Chem. 2005, 1781; (c) Schmidt, A.; Gholipour Shi-
labin, A.; Nieger, M. Heterocycles 2005, 65, 625.
15. (a) Anderson, W. K.; Friedman, A. E. Can. J. Chem. 1971, 49, 668; (b) Anderson,
W. K.; Friedman, A. E. Org. Mass Spectrom. 1972, 6, 797.
16. (a) Edward, J. T.; Sheffler, R. H. J. Org. Chem. 1985, 50, 4855; (b) Krollpfeifer, F.;
Schneider, K. Justus Liebigs Ann. Chem. 1937, 530, 34; (c) Wieland, H.; Hettche,
O.; Hoshino, T. Chem. Ber. 1928, 61, 2371; (d) Besthorn, E.; Ibele, J. Chem. Ber.
1904, 37, 1236.
17. Ichinari, M.; Sato, T.; Hayase, Y. Heterocycles 1988, 27, 227.
18. Edstrom, E. D.; Wei, Y.; Gordon, M. J. Org. Chem. 1994, 59, 2473.
19. Newton, C. G.; Ollis, W. D.; Wright, D. E. J. Chem. Soc., Perkin Trans. 1 1984, 69.
20. Hirota, T.; Katsuta, K.; Namba, T.; Sasaki, K.; Hayakawa, S. J. Heterocycl. Chem.
1985, 22, 187.
(200 MHz, CDCl3):
d
¼1.27 (t, J¼6.9 Hz, 3H, CH2CH3), 2.45 (s, 1H,
NH), 3.55 (s, 2H, CH2), 4.13–4.24 (m, 4H, CH2CH3, CH2), 7.11–7.28 (m,
2H, Harom.), 7.43–7.65 (m, 6H, Harom.), 10.17 (d, J¼6.4 Hz,1H, 5-H). 13
C
NMR (50 MHz, CDCl3):
d¼14.2 (CH2CH3), 50.7 (CH2), 55.4 (CH2),
60.7 (CH2CH3), 102.2 (C-3), 106.7 (C-8), 116.6 (C-6), 127.0 (2C, C-20),
129.3 (C-40), 129.7 (C-5), 129.9 (2C, C-30), 131.8 (C-10), 132.1 (C-7),
136.6 (C-9), 158.2 (C-2), 172.1 (C]O), 185.5 (C]O). IR (KBr):
~
n
¼ 3327, 2978, 1729, 1679, 1599, 1505, 1448, 1241, 1204, 1031, 842,
761, 712 cmꢁ1. MS: m/z (%)¼354 [MþHþ](100), 280 (20), 252 (50),
237 (20), 210 (90), 77 (30). HR-ESI-MS: calcd for: C19H20N3O4:
354.1454; found: 354.1454. Anal. Calcd for C19H19N3O4: C, 62.97; H,
5.56; N, 11.59. Found: C, 63.16; H, 5.38; N, 11.97.
21. (a) Tarumi, Y.; Moriguchi, K.; Atsumi, T. J. Heterocycl. Chem. 1984, 21, 529; (b)
Tarumi, Y.; Takebashi, Y.; Moriguchi, K.; Atsumi, T.; Fukumaru, T.; Yamamoto,
H. J. Heterocycl. Chem. 1980, 17, 1425; (c) Friedrichsen, W.; Schro¨er, W.-D.;
Debaerdemaeker, T. Liebigs Ann. Chem. 1980, 11, 1850; (d) Potts, K. T.; Chen, S. J.
J. Org. Chem. 1977, 42, 1639.
22. Jones, L. H.; Dupont, T.; Mowbray, C. E.; Newman, S. D. Org. Lett. 2006, 8,
1725.
23. Sheldrick, G. M. Acta Crystallogr., Sect. A 2008, 112–122.
References and notes
1. Ollis, W. D.; Stanforth, S. P.; Ramsden, C. A. Tetrahedron 1985, 41, 2239.
2. (a) Padwa, A.; Flick, A. C.; Lee, H. I. Org. Lett. 2005, 7, 2925; (b) Padwa, A.;
Heidelbaugh, T. M.; Kuethe, J. T. J. Org. Chem. 2000, 65, 2368; (c) Sheehan, S. M.;
Padwa, A. J. Org. Chem. 1997, 62, 438.